Natural and Synthetic Lipid nanoparticles and protein corona - A small angle scattering approach

Lipid nanoparticles, whether produced by the body or engineered in the lab, share a common challenge: their structure, composition, and interactions with surrounding proteins determine their biological function, yet these properties remain difficult to resolve at the molecular level. In this talk, I will present a small-angle scattering approach to characterise two paradigmatic systems: high-density lipoproteins (HDL), the body's natural lipid nanoparticles involved in cardiovascular protection, and synthetic mRNA-containing lipid nanoparticles (LNPs) used as gene delivery vehicles.   For HDL, small-angle X-ray scattering (SAXS) combined with cryogenic electron tomography reveals that the main subfractions HDL2a and HDL3 adopt distinct core-shell architectures, with HDL3 displaying an asymmetric protein shell that partially exposes the lipid core. These structural differences correlate with cardiovascular risk status better than standard biochemical markers alone, supporting the idea that HDL "quality" rather than quantity should guide clinical assessment.   For synthetic LNPs, small-angle neutron scattering (SANS) with selective isotopic contrast variation resolves how lipid components are distributed between the core and shell, and how ApoE binding (the first step in the protein corona formation) triggers a structural rearrangement that may drive endosomal escape and mRNA release.   Together, these results illustrate how small-angle scattering, particularly when combined with contrast variation and complementary imaging, provides a uniquely powerful window into the structure-function relationship of lipid nanoparticles in biologically relevant environments.